The technical field of this invention is devices and methods for the diagnosis and treatment of atherosclerosis, and, in particular, devices and methods utilizing receptor proteins associated with atherosclerotic plaques and/or monoclonal antibodies thereto.
Atherosclerosis is a disease which causes the thickening and hardening of the arteries, particularly of the larger arteries. It is characterized by raised fibrous plaques or lesions within the arterial lumen which form as the result of the deposition of plasma cholesterol and low density lipoproteins (LDL).
Key cellular components of the atherosclerotic plaque are foam cells which are derived from phagocytic macrophages of monocytic origin. Macrophages and foam cells have surface receptor proteins which have an affinity for circulating LDL, and which are directly responsible for the receptor-mediated ingestion, or endocytosis, of such material.
These cells also have a receptor-mediated ability to bind and endocytose chemically modified LDL, such as acetylated-LDL (Ac-LDL), acetoacetylated LDL (AcAc-LDL), and oxidized LDL (Ox-LDL), as well as a limited range of other negatively charged macromolecules. This receptor activity has been found to be inducible in monocytes and macrophages under certain conditions, and has been implicated in the formation of foam cells, and hence of atherosclerotic plaques (Goldstein et al. vol. 76, Proc. Natl. Acad. Sci. (USA), pp. 333-337 (1980); Brown et al. vol. 52, Ann. Rev. Biochem., pp. 222-226 (1983)).
The injuries or deformities of the arterial lumen caused by the plaque and associated deposits result in occluded blood flow, and ultimately in a number of related conditions if left untreated, such as, angina, cerebral ischemia, renal hypertension, ischemic heart disease, stroke, and diseases of other organs. Coronary atherosclerosis is still the leading cause of death in the United States and in other industrially advanced countries.
Unfortunately, there are no existing diagnostic methods which can reliably detect these diseases. The early stages of atherosclerosis and related vascular diseases often have no clinical manifestations. Because lifestyle changes, drug therapy, and other means exist for delaying or reducing vascular occlusion or the stresses on various body organs which result from atherosclerotic lesions, the early detection of atheromatous plaques would be of considerable value in permitting preventive intervention at a time when it can be most effective.
Arteriography is the conventional approach to diagnosing advanced vascular disease. This procedure involves the imaging of obstructions in the arteries via catheterization and the injection into the bloodstream of radioopaque substances. However, significant morbidity can result from this procedure due to the increased chances of infection, perforation of the artery, arrhythmia, stroke, and infarction. Because of the risks involved, arteriograms typically are reserved for individuals with advanced or acute atherosclerotic disease, ruling out this method for preventative therapy.
A variety of less invasive techniques for the diagnosis of vascular injury and disease have been used. These techniques include plethysmography, thermography, and ultrasonic scanning. (For a review of these procedures, see Lees and Myers, Vol. 27, Adv. Int. Med., pp. 475-509 (1982)). However, none of these imaging techniques have achieved clinical acceptance.
Other non-invasive approaches to the diagnosis of vascular injury include the administration of injectible, detectible agents to the vascular system of a patient which are capable of recognizing, binding to, and/or being internalized by, atherosclerotic lesions. Such procedures include the administration of hematoporphyrin (as described in U.S. Pat. No. 4,577,636, issued to Spears), monoclonal antibodies (EPO 85402359.5 issued to Takano), or magnetic particles capable of being inductively heated (as described in U.S. Pat. No. 4,359,453 issued to Gordon).
Because LDL is known to be deposited in atherosclerotic plaques, methods employing labelled LDL have been utilized to target plaques (see, for example, U.S. Pat. Nos. 4,647,445 and 4,660,563 issued to Lees). A disadvantage to these methods is that several days are typically required to isolate LDL from the patient's blood and to label them. Often, such a delay in diagnosis and subsequent treatment is detrimental for critically ill patients. Furthermore, an additional risk of viral infection can arise if donor blood is employed as an LDL source.
Consequently, there exists a need for better non-invasive techniques and reagents capable of detecting, mapping, and treating early, non-stenosing, non-flow-disturbing atherosclerotic arterial lesions.
Accordingly, it is an object of the present invention to provide methods for the early detection of atherosclerosis and other related vascular diseases. It is also an object of the present invention to identify a component of the arterial plaque which is key in detecting and mapping an abnormal region of the vascular system, or a region predisposed to atherosclerosis. Yet another object of the invention is to provide a detection method which is non-invasive. A further object of the present invention is to provide devices and methods for locating and quantitating the extent of arterial plaque build up. Another object is to provide a method for treating atherosclerosis.